Process For Folding Of Drug Coated Balloon

ABSTRACT

Method of coating an expandable member is provided. The method comprises providing an expandable member with a plurality of folds defined therein, the expandable member having a folded configuration and a fully expanded configuration at a rated nominal pressure. The expandable member is inflated to an initial pressure of from 10% to about 300% of nominal pressure. A therapeutic agent is disposed on at least a portion of the expandable member. The expandable member is partially deflated to an intermediate pressure by withdrawing an amount of inflation medium from the expandable member, and by applying an external force to the expandable member.

BACKGROUND OF THE DISCLOSED SUBJECT MATTER

1. Field of the Disclosed Subject Matter

The presently disclosed subject matter is related to coatinginterventional medical devices, and particularly coating of therapeuticagents on an expandable member of a medical device. More particularly,the presently disclosed subject matter relates to a system and methodfor retaining a therapeutic agent on a balloon during folding andassembly of the medical device.

2. Description of Related Subject Matter

Atherosclerosis is a disease affecting arterial blood vessels. It is achronic inflammatory response in the walls of arteries, which is inlarge part due to the accumulation of lipid, macrophages, foam cells andthe formation of plaque in the arterial wall. Atherosclerosis iscommonly referred to as hardening of the arteries, although thepathophysiology of the disease manifests itself with several differenttypes of lesions ranging from fibrotic to lipid laden to calcific.Angioplasty is a vascular interventional technique involvingmechanically widening an obstructed blood vessel, typically caused byatherosclerosis.

During angioplasty, a catheter having a folded balloon is inserted intothe vasculature of the patient and is passed to the narrowed location ofthe blood vessel, at which point the balloon is inflated to a fixed sizeas a result of fluid pressure inside the balloon. Percutaneous coronaryintervention (PCI), commonly known as coronary angioplasty, is atherapeutic procedure to treat the stenotic coronary arteries of theheart, often found in coronary heart disease. In contrast, peripheralangioplasty, commonly known as percutaneous transluminal angioplasty(PTA), generally refers to mechanical widening of blood vessels otherthan the coronary arteries. PTA is most commonly used to treat narrowingof the leg arteries, especially, the iliac, external iliac, superficialfemoral and popliteal arteries. PTA can also treat narrowing of veins,and other blood vessels.

Although the blood vessel is often successfully widened by angioplasty,sometimes the treated wall of the blood vessel undergoes vasospasm, orabrupt closure after balloon inflation or dilatation, causing the bloodvessel to collapse after the balloon is deflated or shortly thereafter.One solution to this abrupt closure is stenting the blood vessel toprevent collapse. A stent is a device, typically a metal tube orscaffold that is inserted into the blood vessel after, or concurrentlywith angioplasty, to hold the blood vessel open.

While the advent of stents eliminated many of the complications ofabrupt vessel closure after angioplasty procedures, within about sixmonths of stenting, a re-narrowing of the blood vessel can form. This isa condition known as restenosis. Restenosis was discovered to be aresponse to the injury of the angioplasty procedure and is characterizedby a growth of smooth muscle cells—analogous to a scar forming over aninjury. To address this condition, drug eluting stents were developed toreduce the reoccurrence of the narrowing of blood vessels after stentimplantation. A drug eluting stent is a metal stent that has been coatedwith a drug that is known to interfere with the process of re-narrowingof the blood vessel (restenosis). Examples of various known drug elutingstents are disclosed in U.S. Pat. Nos. 5,649,977; 5,464,650; 5,591,227,7,378,105; 7445792; 7335227, each of which are hereby incorporated byreference in their entirety. However, a drawback of drug eluting stentsis a condition known as late stent thrombosis, which is an event inwhich blood clots on the stent.

Drug eluting balloons are believed to be a viable alternative to drugeluting stents in the treatment of atherosclerosis. In a study whichevaluated restenosis, and the rate of major adverse cardiac events suchas heart attack, bypass, repeat stenosis, or death in patients treatedwith drug eluting balloons and drug eluting stents, the patients treatedwith drug eluting balloons experienced only 3.7% restenosis and 4.8%MACE (major adverse cardiac events) as compared to patients treated withdrug eluting stents, in which restenosis was 20.8% and 22.0% MACE rate.See PEPCAD II study, Rotenburg, Germany.

However, drug eluting balloons present certain unique challenges. Forexample, the drug carried by the balloon needs to remain on the balloonduring delivery to the lesion site, and released from the balloonsurface to the blood vessel wall when the balloon is expanded at thelesion site. For coronary procedures, the balloon is typically inflatedfor less than one minute, typically about thirty seconds. The ballooncan be expanded for a longer period of time for peripheral proceduresalthough this time rarely exceeds 5 minutes. Due to the short durationof contact of the drug coated balloon surface with the blood vesselwall, the balloon coating must exhibit efficient therapeutic agenttransfer and/or efficient drug release during inflation. Thus, there arechallenges specific to drug delivery via a drug coated or drug elutingballoon that are not presented by a drug eluting stent.

Conventional methods of loading interventional devices with therapeuticagents often require coating the entire surface of the balloon with thetherapeutic agent. Coating of the entire surface can be performed in theinflated condition. For purpose of storage and shipping, as well asdelivery through vasculature, the balloon is folded when deflated.However, once coated with a therapeutic agent, the balloon can becomedifficult to fold and sheath for assembly of the catheter. Further,conventional equipment and processes used to achieve such folding andassembly often cause damage, loss, or contamination of the therapeuticagent, and/or can result in contamination of the equipment.

Alternatively, balloons can be coated with a therapeutic agent while ina folded condition, thereby avoiding the drawbacks listed above.However, applying a coating of a solution to a folded balloon results inonly a partially coated balloon surface area which may not be desirabledepending upon the needs and application. Furthermore, the entiresurface area of a coating applied to the folded balloon is exposed tothe blood stream during the tracking and delivery procedure, thusincreasing the likelihood of losing a significant amount, if not all, ofthe drug coating before positioning the balloon and therapeutic agent atthe desired location to commence treatment.

Thus there remains a need, and an aim of the disclosed subject matter isdirected towards, a method with corresponding apparatus for assembly ofan expandable member having one or more therapeutic agents coatedthereon in such a manner that does not result in damage or loss oftherapeutic agent, nor significant contamination of the equipmentemployed. Additionally, the disclosed subject matter provides aprocessing method for expandable member memory retention.

SUMMARY OF THE DISCLOSED SUBJECT MATTER

The purpose and advantages of the disclosed subject matter will be setforth in and apparent from the description that follows, as well as willbe learned by practice of the disclosed subject matter. Additionaladvantages of the disclosed subject matter will be realized and attainedby the methods and systems particularly pointed out in the writtendescription and claims herein, as well as from the appended drawings.

To achieve these and other advantages and in accordance with the purposeof the disclosed subject matter, as embodied and broadly described, thedisclosed subject matter includes a system and method for assembly of anexpandable member having one or more therapeutic agents coated thereonin such a manner that does not result in damage or loss of therapeuticagent, nor significant contamination of the equipment employed.

In accordance with an aspect of the disclosed subject matter, a methodof coating an expandable member is provided. In one embodiment, theexpandable member is a balloon member of a catheter. The method includesproviding an expandable member with a plurality of folds definedtherein, with the expandable member having a folded configuration and afully expanded configuration at a rated nominal pressure. The expandablemember is inflated to an initial pressure of from about 10% to about300% of the nominal pressure. The initial pressure is preferably fromabout 20% to about 100% of nominal pressure. In one embodiment, duringthe inflation, initial pressure of the expandable member is less thannominal pressure. In one embodiment, the initial pressure is from about20% to about 40% of nominal pressure. In one embodiment, the nominalpressure is about 6 atmospheres to about 8 atmospheres. A therapeuticagent is disposed on at least a portion of the inflated expandablemember. The expandable member is partially deflated to an intermediatepressure of from about 10% to about 50% of nominal pressure bywithdrawing an initial amount of inflation medium from the expandablemember, and applying an external force to the expandable member. Thepreferred intermediate deflation pressure is from about 10% to about 20%of nominal pressure. Preferably, the initial amount of inflation mediumis withdrawn simultaneously with the application of an external force.In one embodiment, the inflation medium is a gas.

The therapeutic agent can be applied by spraying, dipping, syringecoating, electrospinning, electrostatic coating, direct coating, or acombination thereof. The therapeutic agent can be selected from thegroup consisting of everolimus, zotarolimus, rapamycin, biolimus,myolimus, novolimus, deforolimus, tacrolimus, temsirolimus,pimecrolimus, paclitaxel, protaxel, taxanes or a combination thereofalthough other fluids and therapeutic agents are contemplated.

In accordance with another aspect of the invention, withdrawing theinflation medium includes using a syringe pump. Withdrawing inflationmedium includes allowing the inflation medium to release from theexpandable member. In some embodiments, withdrawing inflation mediumoccurs at a rate of approximately 2 ml/min or less. Additionally, theintermediate pressure is from about 10% to about 50% of nominalpressure. In one embodiment, the intermediate pressure is from about 10%to about 20% of nominal pressure.

An external force can be applied to the expandable member mechanically,hydraulically or pneumatically, e.g. by a stent crimper. The externalforce can be applied as a substantially uniform force, applied at selectlocations of the expandable member, and/or include a torsionalcomponent. In one embodiment, the external force is applied to theexpandable member by a stent crimper in the range of from about 0.2 toabout 0.25 PSI per mm of the expandable member length.

After partially deflating the expandable member, a remaining amount ofinflation medium can be withdrawn from the expandable member. Forexample, withdrawing the remaining amount of inflation medium can occurby drawing a vacuum on the expandable member using a vacuum box orindeflator. In some embodiments, after partially deflating theexpandable member, at least a portion of the expandable member can becovered with or inserted into a sheath. A mandrel can be inserted withina lumen of the expandable member during coating and/or refolding of theexpandable member.

Additionally, the disclosed subject matter includes a system for coatingan expandable member having a plurality of folds defined therein, thesystem comprising an inflator to inflate an expandable member to aninitial pressure, the initial pressure being from about 10% to about300% of a rate nominal pressure; and a dispenser to dispose atherapeutic agent on at least a portion of an expandable member inflatedto the initial pressure. A deflation station is provided to partiallydeflate an expandable member by reducing the pressure within theexpandable member to an intermediate pressure. The deflation assembly isconfigured to withdraw an amount of inflation medium from the inflatedexpandable member and to apply an external force to an expandablemember. The system can further include a mandrel within a lumen of theexpandable member.

The disclosed subject matter also includes a medical device comprisingan expandable member with a plurality of folds defined therein, theexpandable member having a folded configuration and an expandedconfiguration at a rated nominal pressure, the expandable member havinga surface with a coating of therapeutic agent on at least a portionthereof. The coating can be applied on the surface by inflating theexpandable member to an initial pressure of from about 10% to about300%, disposing a therapeutic agent on at least a portion of theexpandable member, and partially deflating the expandable member.Partially deflating the expandable member includes withdrawing an amountof inflation medium from the expandable member and applying an externalforce to the expandable member.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and are intended toprovide further explanation of the disclosed subject matter claimed.

The accompanying drawings, which are incorporated in and constitute partof this specification, are included to illustrate and provide a furtherunderstanding of the method and system of the disclosed subject matter.Together with the description, the drawings serve to explain theprinciples of the disclosed subject matter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of an expandable member catheter inaccordance with the disclosed subject matter.

FIG. 1A is a schematic cross-sectional view taken along lines A-A inFIG. 1.

FIG. 1B is a schematic cross-sectional view taken along lines B-B inFIG. 1.

FIG. 2 is flow chart of the method in accordance with the disclosedsubject matter.

FIG. 3 is a schematic axial view of an expandable member folded withuneven folds referred to as “pancaking”.

FIGS. 4A-B are schematic axial views of an expandable member which isrefolded without application of an external force of the disclosedsubject matter.

FIGS. 5A-B are schematic axial views of an expandable member which isrefolded with application of an external force of the disclosed subjectmatter.

FIG. 6 is a graphical representation of the coating content of theexpandable member after a sterilization process.

FIG. 7 is a graphical representation of the coating content of thesheath after a sterilization process.

FIG. 8 is a schematic representation of a iris for imparting an externalforce in accordance with the disclosed subject matter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Reference will now be made in detail to the preferred embodiments of thedisclosed subject matter, examples of which are illustrated in theaccompanying drawings. The method and corresponding steps of thedisclosed subject matter will be described in conjunction with thedetailed description of the system.

The methods and systems presented herein can be used for manufacture andassembly of medical devices, such as a drug coated balloon catheterhaving an expandable member with a folded configuration and a fullyexpanded configuration at a rated nominal pressure. The disclosedsubject matter is particularly suited for coating and retaining atherapeutic agent on a folded expandable member of a medical device,without damage to the coating, during folding of the expandable memberand assembly of the medical device. While the disclosed subject matterreferences application of a fluid, e.g. therapeutic agent, it is to beunderstood that a variety of coatings including polymeric, therapeutic,or matrix coatings, can be applied to various surfaces of medicaldevices, as so desired.

In accordance with the disclosed subject matter, a method of coating andfolding an expandable member is provided. The method includes providingan expandable member with a plurality of folds defined therein, whereinthe expandable member has a folded configuration and a fully expandedconfiguration at a rated nominal pressure. It is preferable that theselect inflation pressure be sufficient to expose the surfaces of theexpandable member desired to be coated. Particularly, it is beneficialto apply the coating to a fully inflated expandable member since a fullyinflated expandable member provides a larger surface area to which acoating can be applied, thus allowing for a greater amount and efficacyof coating. Although various fluids are suitable for use in accordancewith the disclosed subject matter, it is advantageous to employ agaseous medium (e.g. air, oxygen, nitrogen, etc.) to ensure that thereis no film or residue retained on the interior walls of the expandablemember which can adversely affect the refolding process and final weightof the expandable member. Preferably, the expandable member is inflatedat an initial pressure which is a percentage of a nominal inflationpressure, such as from about 20 to about 40% of nominal pressure, for agiven balloon size/material. A coating is disposed on at least a portionof the expandable member.

In accordance with an aspect of the disclosed subject matter, and inorder to realize the benefits of the expandable members described above,the initial inflation pressure is at least partially released ordecreased to an intermediate pressure such that the expandable member ispartially refolded after the desired coating is applied to theexpandable member. The expandable member is partially deflated to anintermediate pressure by withdrawing an amount of inflation medium fromthe expandable member and applying an external force to the expandablemember. For example, a select amount of inflation fluid or pressure,which is less than the initial inflation pressure contained within theexpandable member during the coating process, is released or reduced toan intermediate pressure.

For purpose of explanation and illustration, and not limitation anexemplary embodiment of a medical device having an expandable member isshown schematically in FIGS. 1A-B. Particularly, and as illustrated, themedical device embodied herein is a balloon catheter 10, which includesan elongated catheter shaft 12 having a proximal end and having a distalend and an expandable member 30 located proximate the distal end of thecatheter shaft. The expandable member, or balloon as depicted herein,has an outer surface and an inner surface disposed at the distal endportion of the catheter shaft. In accordance with the disclosed subjectmatter, a coating is applied to at least a portion of the outer surfaceof the balloon.

The elongated catheter shaft 12 comprises an outer tubular member 14 andan inner tubular member 16. The outer tubular member 14 defines aninflation lumen 20 disposed between the proximal end portion and thedistal end portion of the catheter shaft 12. Specifically, asillustrated in FIG. 1A, the coaxial relationship of this representativeembodiment defines an annular inflation lumen 20 between the innertubular member 16 and the outer tubular member 14. The expandable member30 is in fluid communication with the inflation lumen 20. The inflationlumen can supply an inflation medium under positive pressure and canwithdraw the inflation medium, i.e. provide negative pressure, from theexpandable member. The expandable member 30 can thus be inflated anddeflated. The elongated catheter is sized and configured for deliverythrough a tortuous anatomy, and can further include a guidewire lumen 22that permits it to be delivered over a guidewire 18. As illustrated inFIG. 1A, the inner tubular member 16 defines the guidewire lumen 22 forthe guidewire 18. Although FIGS. 1 and 1 b illustrate the guidewirelumen as having a coaxial over-the-wire (OTW) construction, theguidewire lumen can be configured as dual lumen over-the-wire (OTW) or arapid-exchange (RX) construction, as is well known in the art.

A wide variety of balloon catheters and balloon constructs are known andsuitable for use in accordance with the disclosed subject matter. Forexample, the expandable member can be made from polymeric material suchas compliant, non-compliant or semi-compliant polymeric material orpolymeric blends. Examples of such suitable materials include, but arenot limited to, nylon 12, nylon 11, nylon 9, nylon 6, nylon 6/12, nylon6/11, nylon 6/9, and nylon 6/6, polyurethane, silicone-polyurethane.Examples of other balloon and catheter embodiments which can be employedin accordance with the disclosed subject matter include U.S. Pat. Nos.4,748,982; 5,496,346; 5,626,600; 5,300,085, 6,406,457 and applicationSer. Nos. 12/371,426; 11/539,944; 12/371,422, each of which is herebyincorporated by reference in their entirety.

In accordance with the disclosed subject matter, any of a variety offluid compositions can be applied to the expandable member. For example,the fluid can include a therapeutic agent for treatment of tissue.Examples of suitable therapeutic agents include anti-restenosis, pro- oranti-proliferative, anti-inflammatory, antineoplastic, antiplatelet,anti-mitotic, anti-coagulant, anti-fibrin, cytostatic, cytoprotective,ACE inhibiting, cardioprotective, antithrombotic, antimitotic,antibiotic, antiallergic and antioxidant compounds. Such therapeuticagents can be, again without limitation, a synthetic inorganic ororganic compound, a protein, a peptide, a polysaccharides and othersugars, a lipid, DNA and RNA nucleic acid sequences, an antisenseoligonucleotide, an antibodies, a receptor ligands, an enzyme, anadhesion peptide, a blood clot agent including streptokinase and tissueplasminogen activator, an antigen, a hormone, a growth factor, aribozyme, and a retroviral vector. Preferably, however, the therapeuticagents include, cytostatic drug. The term “cytostatic” as used hereinmeans a drug that mitigates cell proliferation but allows cellmigration. These cytostatic drugs, include for the purpose ofillustration and without limitation, macrolide antibiotics, rapamycin,everolimus, zotarolimus, biolimus A9, deforolimus, AP23572, tacrolimus,temsirolimus, pimecrolimus, structural derivatives and functionalanalogues of rapamycin, structural derivatives and functional analoguesof everolimus, structural derivatives and functional analogues ofzotarolimus and any marcrolide immunosuppressive drugs. The term“antiproliferative” as used herein means a drug used to inhibit cellgrowth, such as chemotherapeutic drugs. Some non-limiting examples ofantiproliferative drugs include taxanes, paclitaxel, and protaxel.

Additionally or alternatively, the fluid can include other compounds oradditives, such as binding agents, plasticizers, solvents, surfactants,additives, fillers, and the like. Examples of possible compounds includezotarolimus, polyvinylpyrrolidone and glycerol. In one embodiment thetherapeutic agent can be provided in liquid form or dissolved in asuitable solvent. In another embodiment, therapeutic agent is providedas a particulate and mixed in a suitable carrier for application as afluid.

In accordance with the disclosed subject matter, the expandable memberof the medical device has a plurality of folds defined therein. Forexample, a number of conventional balloon catheters include such folds,so as to have a folded configuration and a fully expanded configuration.Generally, the formation of folds can be performed using heat andpressure to form or define creases in the material of the balloon.Examples of such folded balloons are disclosed, for purpose ofillustration in U.S. Pat. Nos. 6,494,906; 6,478,807; and 5,911,452, eachof which is hereby incorporated by reference in their entirety.

Particularly, a plurality of folds or pleats are initially imparted intoa expandable member of a catheter by any means known in the art. This isaccomplished by processing the expandable member in a pleat head thatimparts a plurality of folds or pleats into the expandable member. Afterthis, the pleated expandable member is processed in a fold head wherethe pleats are wrapped in on direction and compressed to reduce theoverall profile. For example, the processing can be performed by anautomated table top pleat and folder manufactured by Machine SolutionsInc. (MSI), MSI Balloon Form/Fold/Set Machine WS1275-101. In oneembodiment, five folds of equivalent surface area are imparted into theexpandable member which result in a symmetrical shape when in thefolded, i.e. uninflated, configuration. Although the exemplaryembodiment illustrated in the drawings depicts five folds, it is to beunderstood that the number and size of the folds can vary, as sodesired, to expandable members of various dimensions and shapes. Thefolded configuration provides a reduced profile which facilitatesassembly, storage and shipping of the catheter. Additionally, thereduced profile of the folded expandable member improves thedeliverability and trackability of the catheter through the vascularanatomy.

The expandable member is inflated to an initial pressure of from about10% to about 300% of nominal pressure. The initial pressure ispreferably from about 20% to about 100% of nominal pressure. In oneembodiment, during the inflation, initial pressure of the expandablemember is less than nominal pressure. In one embodiment, the initialpressure is from about 20% to about 40% of nominal pressure. In oneembodiment, the nominal pressure is about 6 atmospheres to about 8atmospheres.

With the desired number of folds imparted in the expandable member, theexpandable member is inflated to an initial pressure of from about 20%to about 40% of nominal pressure, and fluid such as a therapeutic agentis disposed thereon. To assist with the application of the therapeuticagent on the surface of the expandable member, a mandrel can be insertedwithin the guidewire lumen 22. The mandrel can be constructed from avariety of materials, e.g. metal, metal alloys, and polymeric materialshaving sufficient rigidity to maintain the catheter in a linearalignment. In this regard, the mandrel serves to inhibit or preventbowing or warping of the catheter and expandable member. Accordingly,the expandable member is maintained in a consistent and linear alignmentabout the longitudinal axis of the catheter, which in turn can allow fora uniform coating of therapeutic agent along the desired length of theexpandable member. Furthermore, maintaining the expandable member in afixed profile and linear alignment can assist in minimizing waste oftherapeutic agent during the coating process, e.g., spraying, dipping,direct fluid coating, etc. If coating is to be performed on an assembledcatheter, the mandrel can have a length to extend the entire length ofthe catheter and an outer diameter sized to be positioned within theguidewire lumen 22.

One or more coatings can be applied to the select portions of themedical device by processes such as spraying, dipping, syringe coating,electrospinning, electrostatic coating, direct coating, direct fluidapplication as disclosed in application Ser. No. 61/345,575,combinations thereof, or other means as known to those skilled in theart. The coating can be applied over at least a portion or the entiretyof the expandable member or medical device in non-uniform, or uniformconcentrations and/or patterns. The coating characteristics can beaffected by process variables. For example, for dip-coating process,coating quality and thickness can vary as an effect of variables such asnumber, rate, and depth of dips along with drying time and temperature.Accordingly, the variables of the particular coating process employedcan be controlled to achieve the desired coating characteristics. By wayof example, and not limitation, certain coating processes that can beused with the instant invention are described in U.S. Pat. No. 6,669,980to Hansen; U.S. Pat. No. 7,241,344 to Worsham; and U.S. Publication No.20040234748 to Stenzel, the disclosures of which are hereby incorporatedby reference in their entirety.

In accordance with the disclosed subject matter, the expandable memberis partially or fully inflated to an initial pressure of from about 20%to about 40% of nominal pressure when the fluid is disposed thereon. Theextent in which the expandable member is inflated will depend at leastin part on the amount of inflation medium selected for initialinflation. It therefore is preferable that the select amount ofinflation medium be sufficient to expose the surfaces of the expandablemember desired to be coated. Particularly, it is beneficial to apply thecoating to a fully inflated expandable member since a fully inflatedexpandable member provides a larger surface area to which a coating canbe applied, thus allowing for a greater amount and efficacy of coating.Although various fluids are suitable for use in accordance with thedisclosed subject matter, it is advantageous to employ a gaseous medium,e.g. air, to ensure that there is no film or residue retained on theinterior walls of the expandable member which can adversely affect therefolding process and final weight of the expandable member.

In accordance with an aspect of the disclosed subject matter, and inorder to realize the benefits of the reduced profile expandable membersdescribed above, the expandable member is refolded after the desiredcoating is applied to the expandable member. To avoid detrimental impactto the applied coating during the refolding process, the expandablemember is first partially deflated to an intermediate pressure bywithdrawing an initial amount of inflation medium and applying anexternal force to the expandable member. Particularly, an amount offluid, which is less than the select amount of fluid contained withinthe expandable member during the coating process, is withdrawn from theexpandable member to partially deflate the expandable member. Theexternal force is applied to the outer surface of the expandable member,preferably simultaneously while withdrawing the initial amount ofinflation medium, to facilitate the deflation and provide acircumferential constraint on the expandable member. The interaction ofthe initial, intermediate, or deflation and the application of theexternal force effect the reformation of the previously defined foldsand ensure a symmetrical expandable member profile when in the deflatedconfiguration. Further, and as discussed above, a mandrel can beinserted into the guidewire lumen 22 of the catheter. The mandrel servesto inhibit or prevent bowing or warping of the catheter and expandablemember, and maintains the diameter and shape of the expandable member ismaintained during exposure to the external force. Accordingly, theexpandable member is maintained in a consistent and linear alignmentabout the longitudinal axis of the catheter, which in turn allows thetherapeutic agent to dry in a consistent and uniform fashion on thesurface of the expandable member, thus maximizing the efficacy of thetherapeutic agent. The mandrel can be configured to extend at least thelength of the expandable member, and an outer diameter for positioningwithin the guidewire lumen 22.

The release of the amount of fluid, or inflation pressure, can beperformed by exposing the expandable member to ambient conditions. Thatis, the expandable member in its partially expanded configuration andinitial inflation pressure will have an elevated pressure as compared tothe ambient conditions. Accordingly, upon release of the initial amountof fluid, or initial inflation pressure, by exposure to the ambientconditions, the pressure differential will cause at least some of theamount of fluid contained within the expandable member to exit andreduce the pressure within the expandable member to an intermediatepressure.

The intermediate pressure is from about 10% to 50% of nominal pressure,and preferable, the intermediate pressure is from about 10% to about 20%of nominal pressure.

Thus, the expandable member will partially deflate and partially refoldwith minimal surface tension exhibited on the coating disposed on thesurface of the expandable member. The operater can perform an analysisto determine if drug retained on expandable member meets minimumcriteria, for example, visual inspection for checking bare spots on theexpandable member.

Additionally, or alternatively, a negative pressure, for example,between about 0.1 atmosphere (atm) to about 0.25 atm, can be drawn onthe expandable member to reduce the pressure to an intermediate pressureand thus partially deflate the expandable member. In embodiments inwhich a negative pressure is applied to release the initial amount offluid, or reduce the initial inflation pressure to the intermediatepressure, the negative pressure is less than the vacuum pressurerequired to withdraw the entire amount of fluid, or initial inflationpressure, in the expandable member and thus return the expandable memberto the completely folded or collapsed condition. The pressure of theexpandable member can be controlled to be independently optimized suchthat the rate of inflation and/or depressurization can be adjustedeither continuously or via a step-wise function.

For purpose of withdrawing an amount of inflation medium, a number ofknown techniques can be used. For example, and as embodied herein, adeflation device such as a syringe pump, having a gas-tight syringe canbe attached to the inflation lumen of the expandable member. Thedeflation device allows for automated, repeatable, and controlled amountof fluid withdrawn by volume from the expandable member. This isadvantageous since it reduces or eliminates the variability inherent ina human operator controlled method or apparatus. Alternative devices andtechniques can be used for withdrawing desired amounts of inflationmedium. Withdrawing inflation medium can occur at a rate ofapproximately 2 ml/min or less.

With regard to the application of external force on the expandablemember, a variety of known techniques can be used. Particularly, theexternal force can be applied mechanically, hydraulically orpneumatically. For example, pneumatic force can be applied using apressure chamber of suitable construct to induce a positive pressure onthe external surface of the expandable member. Similarly, hydraulicpressure can be applied using suitable liquid that will not interactwith the applied coating, or by providing a sheath to protect theapplied coating. In this manner, the external force can be applied assubstantially uniform pressure across the surface of the expandablemember.

As embodied herein, for purpose of illustration and not limitation, theexternal force is applied mechanically. In this manner the externalforce can include a torsional component to assist with the wrapping andfolding of the folds. Furthermore, if desired, the mechanical force canbe applied at select locations to minimize any risk of damage to thecoating while obtaining the advantage of the external force. Forexample, a stent crimper or similar apparatus can be used for applyingan external force. The stent crimper includes a plurality of jaws whichallow for circumferential constraint of the expandable member. The jawsof the stent crimper can be configured to circumscribe the entire outersurface of the expandable member, or alternatively, have discrete pointsof contact with the expandable member. For example, a stent crimper canapply an external force to an expandable member with a rate of fromabout 0.2 to about 0.25 psi per mm of the expandable member.Alternatively, the external force can be applied using a plurality ofblades and configured with a cam or actuator to contract the blades inunison, i.e. simultaneously, such as an iris as illustrated in FIG. 8.The blades can be arranged to contact the expandable member over theentire working length of the expandable member, or alternatively, atdiscrete locations.

Accordingly, the jaws or blades can exert a substantially uniform ornon-uniform force along the expandable member, as so desired. In thismanner, the stent crimper, or other suitable device, represents the solepiece of equipment which contacts the coating disposed on the expandablemember. As compared to prior art techniques, this discrete point ofcontact is advantageous as it minimizes the risk of damage ordegradation to the coating surface. As previously noted, it ispreferable for the external force to be applied simultaneously whilewithdrawing the initial amount of inflation medium. Similarly, it ispreferred that such application of external force be performed uniformlythroughout the withdrawing process, but with only sufficient force torefold the folds of the expandable member. The external force preferablyshould not overcome the withdrawing process, i.e., the external forceshould not force inflation medium from the expandable member orotherwise crush the expandable member.

For purpose of example, and again with reference to the stent crimper,it is suitable to use a lever arm to actuate the jaws to close viagravitational forces. This is advantageous in that it results in minimalforce on the expandable member, and relatively low pressure andtemperature acting on the coating to thereby minimize the risk of damageor degradation of the coating. Alternatively, the jaws can be actuatedhydraulically or pneumatically to induce a greater force on theexpandable member, if so desired.

Further in accordance with the disclosed subject matter, a remainingamount of inflation medium is withdrawn after partially deflating theexpandable member. For example, and as embodied herein, an indeflator orvacuum box is provided to draw a vacuum on the expandable member. Theindeflator or vacuum box is placed in fluid communication with theinflation lumen of the expandable member, after partial deflation of theexpandable member by withdrawing an initial amount of fluid medium andapplication of an external force as described above, a remaining orresidual fluid is withdrawn to return the expandable member to thefolded configuration.

Reference will now be made to the system of the disclosed subjectmatter, and the operation of the system. Particularly, and for purposeof illustration and not limitation, a suitable system for performing themethod previously described includes the following.

In operation, a 5 cc glass tight syringe pump of the deflation device isattached to a 3-way stopcock, with the two remaining ports beingattached to the vacuum source and catheter, respectively. The stopcockis open to the syringe and the proximal inflation luer of the catheterto establish a closed system. The jaws of the closure device, e.g. stentcrimper, are opened to receive the inflated expandable member therein.The jaws can be configured to receive a variety of expandable memberdiameters, and extend a length equal to or greater than the length ofthe expandable member.

As disclosed above, the jaws serve to circumferentially constrain theexpandable member. This constraint prevents any portions of theexpandable member from collapsing or refolding unevenly or “pancaking”which results in an asymmetrical profile, and uneven expansion rate ofthe folds upon expandable member inflation within the lumen.Additionally, the circumferential constraint prevents undesired bowingor sagging of the expandable member along its longitudinal axis. Anexample of this uneven refolding or “pancaking” is illustrated in FIG.3. To further minimize or prevent “pancaking” and assist in returningthe initial folds to their original direction, the external forceapplied by the jaws can include a torsional component which wraps orrolls the folds in an overlapping manner to minimize the profile of theexpandable member.

Upon closure of the jaws around the inflated expandable member andapplication of the constraining force on the outer surface of theexpandable member, the deflation device gradually withdraws apredetermined amount of fluid from the expandable member at apredetermined rate to partially deflate the expandable member. In otherwords, the withdrawal of the amount of fluid and the application of theexternal force occurs simultaneously. The particular amount and rate ofwithdrawal can vary depending on the coating properties. For example, avolume of about 0.75 ml of fluid can be withdrawn at a rate of about 2ml/min or less for a 6×40 mm balloon. In accordance with the disclosedsubject matter, the initial amount of fluid withdrawn is about 60-80% ofthe fluid required to inflate the expandable member to the fullyexpanded configuration at a rated nominal pressure.

As the deflation device is arranged to only partially deflate theexpandable member, the amount of fluid withdrawn from the expandablemember is less than the total amount of fluid contained within theexpandable member when in the inflated configuration.

After partially deflating the expandable member by withdrawing theinitial amount of fluid and closure of the jaws, the expandable membercan be inspected to ensure proper refolding has occurred and no“pancaking” effects are present. FIGS. 4A-B provide an illustrativeexample of a expandable member which is refolded without the closuredevice, e.g. stent crimper. By comparison, FIGS. 5A-B provide anillustrative example of a expandable member which is refolded with theclosure device, e.g. stent crimper in accordance with the disclosedsubject matter. As is evident, the expandable member of FIGS. 5A-B whichis refolded in accordance with the disclosed subject matter achieves aneven and symmetrical, i.e. cylindrical, shape. In the event thatpancaking effects are detected during the inspection, the expandablemember can be inflated again and the above-described process can berepeated to achieve an even, symmetrical refolded expandable member. Inthis regard, the disclosed subject matter is advantageous in that itallows for “pancaked” expandable members to be “re-worked” orreprocessed to achieve the proper symmetrical shape rather thandiscarded.

If no “pancaking” is detected, the vacuum source can be activated towithdraw the remaining amount of fluid within the expandable member tofully collapse the expandable member. In some embodiments a sheath canbe placed over the expandable member. In such embodiments, one end ofthe sheath can be flared, in order to facilitate insertion of theexpandable member therein and avoid any undesired snagging, and placedover the distal end of the expandable member. Additionally, a lubriciouscoating can be applied to reduce the frictional forces, provided thelubrication employed does not interfere or compromise the efficacy ofthe therapeutic agent. The sheath is slid over the expandable member adesired distance, until significant resistance is felt. Once the sheathis in the desired position, the stopcock is opened to the vacuum source,e.g. indeflator and a full vacuum is pulled to remove all residual fluidin the expandable member. The remainder of the sheath can then beadvanced over the expandable member to ensure that no wrinkles orunwanted folds are present and that the drug coating is protected.

The methods and apparatus of the disclosed subject matter provide anadditional benefit in terms of drug recovery from the folded expandablemembers. FIG. 6 shows data from devices that were processed using themethods disclosed. The graph depicts total drug content on the balloonafter the sheath is removed and demonstrates that minimal drug is lostfrom the method disclosed herein. Current specifications for drugcontent are +/−20% from a 100% target. It is possible that particularsamples have more than 100% drug as there is acceptable variability onthe method for which the coating is deposited as well as acceptablevariability on the analytical method used to determine drug content.

In accordance with another aspect of the disclosed subject matter, thefully assembled catheter can undergo a sterilization process. Forpurpose of evaluation, a study was performed to determine theeffectiveness of the presently disclosed method and system. A group ofNylon/Pebax 72D blend balloons (size 6−40 mm) were tested in this study.A 600 μg/cm² dose of zotarolimus/poly(N-vinyl pyrrolidone)(PVP)/glycerol(ZPG) formulation was applied to the balloons. After sterilization, theexpandable member and sheath were removed from the catheter and areindependently analyzed to determine the coating content, i.e., theamount of coating retained on the surface as a percentage of the totalamount of coating dispensed during application of the coating to theexpandable member. FIGS. 6-7 graphically depict the coating content ofthe expandable member and sheath, respectively, for a representativeexample performed using the method and system previously described. Asillustrated, the method and apparatus of the disclosed subject matterprovide about 90-100% drug recovery on the expandable member itself,while less than about 2% of the drug is retained on the sheath.

In accordance with in the disclosed subject matter, an endoprosthesis,e.g. stent, can be mounted on the expandable member. The type of stentthat can be used includes, but is not limited to, bare metal stent, drugeluting stent, prohealing stent, and self-expanding vulnerable plaqueimplant. The stent coating can contain the same or different therapeuticagents from the catheter or expandable member. Similarly, the coating onthe catheter or expandable member can have the same or distinct releasekinetics from the therapeutic coating on the stent. The coating appliedto the expandable member can be allowed to dry prior to placement of thestent thereon.

Alternatively, the coating could not be allowed to dry or cure past a“tacky” state before the stent is positioned and/or crimped onto it.This would enable the adhesion of the coating on the expandable memberto the inside of the prosthesis. This process increases the retention ofthe prosthesis onto the expandable member (acting as a prosthesisretention enhancer) thus reducing the chance that the stent will move onthe expandable member during the torturous delivery through the vascularlumen.

If desired, and as previously discussed, a protective sheath can beprovided to protect the coating during shipping and storage and/orduring delivery of the coated expandable member through the body lumen.A variety of sheaths are known, including removable sheaths or ballooncovers, retractable sheaths to be withdrawn prior to deployment of theballoon, and elastic sheaths that conform to the balloon upon expansion.Such elastic sheaths are porous or include apertures along a portionthereof. In operation, the inflation of the expandable member causes thesheath to expand for release of the coating and/or therapeutic agentthrough the porous wall or apertures to the tissue of the arterial wall.For example, see U.S. Pat. No. 5,370,614 to Amundson, the disclosure ofwhich is incorporated by reference in its entirety

While the disclosed subject matter is described herein in terms ofcertain preferred or exemplary embodiments, those skilled in the artwill recognize that various modifications and improvements can be madeto the disclosed subject matter without departing from the scopethereof. Moreover, although individual features of one embodiment of thedisclosed subject matter can be discussed herein or shown in thedrawings of the one embodiment and not in other embodiments, it shouldbe apparent that individual features of one embodiment can be combinedwith one or more features of another embodiment or features from aplurality of embodiments.

In addition to the specific embodiments claimed below, the disclosedsubject matter is also directed to other embodiments having any otherpossible combination of the dependent features claimed below and thosedisclosed above. As such, the particular features presented in thedependent claims and disclosed above can be combined with each other inother manners within the scope of the disclosed subject matter such thatthe disclosed subject matter should be recognized as also specificallydirected to other embodiments having any other possible combinations.Thus, the foregoing description of specific embodiments of the disclosedsubject matter has been presented for purposes of illustration anddescription. It is not intended to be exhaustive or to limit thedisclosed subject matter to those embodiments disclosed.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the method and system of thedisclosed subject matter without departing from the spirit or scope ofthe disclosed subject matter. Thus, it is intended that the disclosedsubject matter include modifications and variations that are within thescope of the appended claims and their equivalents.

1. A method of coating an expandable member comprising: providing anexpandable member with a plurality of folds defined therein, theexpandable member having a folded configuration and a fully expandedconfiguration at a rated nominal pressure; inflating the expandablemember to an initial pressure of from about 10% to about 300% of thenominal pressure; disposing a therapeutic agent on at least a portion ofthe expandable member; and partially deflating the expandable member toan intermediate pressure, wherein partially deflating includeswithdrawing an amount of inflation medium from the expandable member;and applying an external force to the expandable member.
 2. The methodof claim 1, wherein the normal pressure is from about 6 to about 8atmospheres.
 3. The method of claim 1, wherein the initial pressure isfrom about 20% to about 100% of nominal pressure.
 4. The method of claim1, wherein the initial pressure of the expandable member is less thannominal pressure.
 5. The method of claim 1, wherein the initial pressureis from about 20% to about 40% of nominal pressure.
 6. The method ofclaim 1, wherein disposing the therapeutic agent is by spraying,dipping, syringe coating, electrospinning, electrostatic coating, directcoating, or a combination thereof.
 7. The method of claim 1, wherein thetherapeutic agent is selected from the group consisting of everolimus,zotarolimus, rapamycin, biolimus, myolimus, novolimus, deforolimus,tacrolimus, temsirolimus, pimecrolimus, paclitaxel, protaxel, taxanes,or a combination thereof.
 8. The method of claim 1, wherein withdrawinginflation medium includes allowing the inflation medium to release fromthe expandable member.
 9. The method of claim 1, wherein withdrawinginflation medium includes using a syringe pump.
 10. The method of claim1, wherein withdrawing inflation medium occurs at a rate ofapproximately 2 ml/min or less.
 11. The method of claim 1, wherein theintermediate pressure is from about 10% to about 50% of nominalpressure.
 12. The method of claim 1, wherein the intermediate pressureis from about 10% to about 20% of nominal pressure.
 13. The method ofclaim 1, wherein the external force is applied to the expandable membermechanically, hydraulically or pneumatically.
 14. The method of claim 1,wherein the external force is applied as a substantially uniform force.15. The method of claim 1, wherein the external force is applied atselect locations of the expandable member.
 16. The method of claim 1,wherein the external force includes a torsional component.
 17. Themethod of claim 1, wherein the external force is applied to theexpandable member by a stent crimper with a rate of from about 0.2 toabout 0.25 psi per min of the expandable member.
 18. The method of claim1, wherein withdrawing inflation medium and applying the external forceoccurs simultaneously.
 19. The method of claim 1, further comprisingafter partially deflating the expandable member withdrawing a remainingamount of inflation medium from the expandable member.
 20. The method ofclaim 19, wherein withdrawing the remaining amount of inflation mediumoccurs by drawing a vacuum on the expandable member.
 21. The method ofclaim 20, wherein the remaining amount of inflation medium is withdrawnby a vacuum box or indeflator.
 22. The method of claim 1, furthercomprising after partially deflating the expandable member covering atleast a portion of the expandable member with a sheath.
 23. The methodof claim 1, wherein the inflation medium is a gas.
 24. The method ofclaim 1, wherein the expandable member is a balloon member of acatheter.
 25. The method of claim 1, further comprising disposing amandrel within a lumen of the expandable member.
 26. A system forcoating an expandable member having a plurality of folds definedtherein, the system comprising: an inflator to inflate an expandablemember to an initial pressure; the initial pressure being from about 10%to about 300% of a rated nominal pressure; a dispenser to dispose atherapeutic agent on at least a portion of an expandable member inflatedto the initial pressure; a deflation assembly at least to partiallydeflate the inflated expandable member to an intermediate pressure, thedeflation assembly configured to withdraw an amount of inflation mediumfrom the inflated expandable member and to apply an external force to anexpandable member.
 27. The system of claim 26, wherein the normalpressure is from about 6 to about 8 atmospheres.
 28. The system of claim26, wherein the initial pressure of the expandable member is from about20% to about 100% of nominal pressure.
 29. The system of claim 26,wherein the initial pressure of the expandable member is less thannominal pressure.
 30. The system of claim 26, wherein the initialpressure of the expandable member is from about 20% to about 40% ofnominal pressure.
 31. The system of claim 26, wherein the dispenser is asprayer, dipper, syringe, electrostatic coating assembly,electrospinning assembly or direct coating assembly.
 32. The system ofclaim 26, wherein the therapeutic agent is selected from the groupconsisting of everolimus, zotarolimus, rapamycin, biolimus, myolimus,novolimus, deforolimus, tacrolimus, temsirolimus, pimecrolimus,paclitaxel, protaxel, taxanes, or a combination thereof.
 33. The systemof claim 26, wherein the deflation assembly includes a syringe pump. 34.The system of claim 26, wherein the deflation assembly withdraws theinitial amount of inflation medium at a rate of approximately 2 ml/minor less.
 35. The system of claim 26, the intermediate pressure is fromabout 10% to about 50% of nominal pressure.
 36. The system of claim 26,the intermediate pressure is from about 10% to about 20% of nominalpressure.
 37. The system of claim 26, wherein the external force isapplied to the expandable member mechanically, hydraulically orpneumatically.
 38. The system of claim 26, wherein the external force isapplied as a substantially uniform force.
 39. The system of claim 26,wherein the external force is applied at select locations to theexpandable member.
 40. The system of claim 26, wherein the externalforce includes a torsional component.
 41. The system of claim 26,wherein the deflation assembly includes a stent crimper with a rate offrom about 0.2 to about 0.25 psi per mm to apply the external force. 42.The system of claim 26, wherein the deflation assembly withdraws theinflation medium and applies the external force simultaneously.
 43. Thesystem of claim 26, further comprising a vacuum source to withdraw aremaining amount of inflation medium from an expandable member.
 44. Thesystem of claim 43, wherein the vacuum source is a vacuum box orindeflator.
 45. The system of claim 26, wherein the inflation medium isa gas.
 46. The system of claim 26, further comprising a mandrel disposedwithin a lumen of the expandable member.
 47. A medical devicecomprising: an expandable member with a plurality of folds definedtherein, the expandable member having a folded configuration and anexpanded configuration at a rated nominal pressure, the expandablemember having a surface with a coating of therapeutic agent on at leasta portion thereof, the coating being applied on the surface by:inflating the expandable member to an initial pressure of from about 10%to about 300% of nominal pressure, disposing a therapeutic agent on atleast a portion of the expandable member, and partially deflating theexpandable member, wherein partially deflating the expandable memberincludes withdrawing an amount of inflation medium from the expandablemember and applying an external force to the expandable member.